The present invention relates to a method and an apparatus for producing a transmucosal potential difference (PD) signal essentially being unaffected by intestinal motor activities. It also relates to different applications of such a signal.
All human tissues are depending on a continuous supply of blood to survive. The tissues control their own supply of blood by releasing substances to expand or contract the nonstriated muscle of the incoming blood vessels. However, these blood vessels also take part in the overall blood pressure regulation, being controlled by the central nervous system (CNS). This regulation works on the principle of maintaining the arterial pressure as constant as possible, which for instance is crucial for the kidneys to work optimally. The human body can modify the mean arterial pressure (MAP) in two ways: by changing the total throughput in the system, which is the cardiac output (CO), i.e. the total blood quantity that the heart pump per time unit, or by changing the total peripheral resistance (TPR), i.e. the total vascular resistance in the system. The following relation for the parameters hold:
MAP=COxc3x97TPR
It can clearly be seen by the above-mentioned relation, that if the MAP is falling and the CO is essentially constant at a normal level, the problem must be in the TPR, and the compensation is to enhance the CO. If, on the other hand, the CO is not constant, but on a low level, the compensation is to enhance the TPR. The body xe2x80x9cmeasuresxe2x80x9d the MAP directly by means of pressure receptors on the arterial side, and the CO with knowledge of the heart frequency, filling pressure and contractility. With the knowledge about CO and MAP the body can xe2x80x9ccalculatexe2x80x9d the TPR and compensate accordingly when the MAP is falling.
In the intensive care it is very common that one or several of these parameters are deranged, and it is of crucial importance for the correct treatment to be aware of the problem. The intensive care physicians have medicines at hand to affect the CO as well as the TPR, and to be able to use these medicines correctly he needs information about at least two of the parameters in the above-mentioned equation. It is, however, difficult, if at all possible, with the current techniques to obtain a continuous registration of anything but the MAP. Access to a continuous recording system is crucially important since it gives the possibility of an xe2x80x9calarm-functionxe2x80x9d which alerts the physician to initiate early compensatory interventions.
The CO can be measured intermittently by introducing a so called PA catheter into the pulmonary artery and estimating the CO from the time-temperature curve of a supplied xe2x80x9ccold pulsexe2x80x9d, a so called thermodilution principle. However, there are several drawbacks with this method, and it is only used in the most severe cases. Moreover, the measurement only gives a momentarily on-the-spot measure, and the measurement can not be repeated more than a few times. Furthermore, catheterization of the heart adds a small but significant risk for complications in these severely ill patients.
There is, as far as the applicant is aware of, no known method to directly measure the TPR with full time resolution. In clinical routine, this parameter is usually only roughly estimated by a subjective evaluation of skin temperature to be xe2x80x9cperipherally warmxe2x80x9d or xe2x80x9cperipherally coldxe2x80x9d.
There is consequently a strong need for a preferably non-invasive method that continuously measures the TPR. A continuous signal would not only make it possible to alert the physician to make early interventions when the patient deteriorates, but could also be used to quantitatively optimize volume substitution, cardiotropic drugs etc.
The most important regulation mechanism for TPR is the activity in the sympathetic nervous system, and one of the most important vascular beds controlled by this system is the gastrointestinal tract, which thus is very important in the blood-pressure regulation.
Intestinal vascoconstriction can, however, also be potentially detrimental, since it can cause damage to the mucous membrane, and render it possible for bacteriaes to translocate to the blood side, which may in turn lead to severe toxaemia, i.e. blood poisoning. If this sequence of events is not detected in time, it is often too late to save the patient""s life. Therefore, there is a strong need for a method for measuring intestinal sympathetic activity not only as an indirect measure of the TPR, but also to diminish the risk for mucosal damage and bacterial translocation.
The transmucosal potential difference (PD) signal reflects the potential generated by chloride secretion in the mucous membrane in the intestine. The principle behind the PD-measurement is illustrated in FIG. 1. Active secretion of chloride, which occurs via a specific ion channel, the CFTR, generates a current across the mucosa that recirculates through the paracellular shunt resistance. The transmucosal potential difference (PD) will consequently depend on both the rate of chloride secretion and the magnitude of the shunt resistance. In isolated tissue in vitro, the ionic current can be measured by short-circuiting the tissue with an external current source, in which case the shunt current becomes zero. The current needed for short-circuiting the membrane, the short-circuit current (SCC), is consequently identical to the membrane current. In vivo, short-circuiting is obviously impossible.
Typical examples of the SCC and PD signal and the effect of sympathetic activation in vitro, i.e. in the absence of motor activity, is shown in FIGS. 2a-d. 
Hence, the size of the PD signal depends on a number of factors, reflecting the condition for the intestinal functions, such as salt transportation ability for the mucous membrane, an undamaged mucosal barrier, correctly working neurogenic control of the epithelium, and level of sympathetic activity. The PD signal is possible to measure relatively easily by the introduction of a thin plastic tube into the upper part of the bowel, and measurement of the potential difference between a perfusion and a similar solution infused subcutaneously. However, a problem with this PD signal is that it is also strongly affected by the intestinal motor activities, i.e. the peristalsis. The magnitude of these changes is relatively large, and it has therefore hitherto been nearly impossible to sort out the sympatethic component of the signal in the presence of intestinal motor activity, and for this reason the PD signal has never actually been applied in clinical practice.
It is therefore an object of the present invention to provide a method and an apparatus for producing a transmucosal potential difference (PD) signal that is essentially unaffected by intestinal motor activities and which therefore reflects intestinal sympathetic activity and TPR. It is also an object of the invention to provide some applications of such a signal.
This object is achieved by the invention such as it is defined in the enclosed claims.